The present invention relates generally to the field of allergies. More particularly, the present invention provides a method for treating an allergy in a subject by inducing tolerance to an allergen associated with the allergy. Medicinal kits useful in protocols to induce tolerance or reduce intolerance in a subject also form part of the present invention.
Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Rates of allergic disease have risen exponentially since 1980. While the prevalence of asthma, eczema and rhinitis may be stabilizing, food allergy and anaphylaxis continue to rise (Gupta et al, Thorax 62(1):91-96, 2007; Robertson et al, Med J Aust 180(6):273-276, 2004). In the UK, hospital admissions for food allergy and anaphylaxis have increased 500% and 700% respectively from 1991 to 2005 (Gupta et al, supra 2007). Prevalence of childhood peanut allergy has doubled between 1997 and 2002 (Sicherer et al, J Allergy Clin Immunol 112(6):1203-1207, 2003). Data from the Australian Institute of Health and Welfare show similar trends (Mullins, Med J Aust 186(12):618-621, 2007). Allergic disorders are now the most common chronic diseases affecting children in Western societies. It is estimated that 5%-8% of children have a food allergy (Bock, Pediatrics 79(5):683-688, 1987; Young et al, Lancet 343(8906):1127-1130, 1994), and 1.5% of children have peanut allergy (Grundy et al, J Allergy Clin Immunol 110(5):784-789, 2002).
Foods are the commonest triggers of severe allergic reactions (anaphylaxis) [Kemp et al, Arch Intern Med 155(16):1749-1754, 1995]. Peanut allergy is of particular concern as reactions to peanuts are usually severe, involving two or more organ systems in 41% of peanut allergic subjects, and involving the respiratory system (anaphylaxis) in 42% of peanut allergic subjects (Sicherer et al, Pediatrics 102(1):199-205, 1998). Reactions to peanuts caused 27% (Pumphrey, Curr Opin Allergy Cin Immunol 4(4):285-290, 2004) to 30% (Bock et al, J Allergy Clin Immunol 107(1):191-193, 2001) of deaths from food induced anaphylaxis. The threshold dose for reaction to peanut is often low—subjective and objective symptoms may be induced by as little as 100 μg (< 1/1000th of a peanut) and 2 mg of peanut protein (< 1/100th of a peanut), respectively (Hourihane et al, J Allergy Clin Immunol 100(5):596-600, 1997). In double blind placebo controlled peanut challenges, 50% of peanut allergic subjects reacted to 3 mg of peanut protein ( 1/100th of a peanut) [Wensing et al, J Allergy Clin Immunol 110(6):915-920, 2002]. Furthermore, subjects with severe reactions to peanut tend to react to lower doses of peanut than those with mild symptoms (Wensing et al, supra 2002). Therefore, most allergic reactions to peanut are severe, reactions may occur to low doses of allergen, and peanut induced reactions account for a large proportion of deaths from food allergy.
Most cases of peanut allergy first present in early childhood between the ages of 14 and 24 months (Sicherer et al, supra 1998). Unlike allergy to milk and egg which generally resolve by late childhood, peanut allergy usually persists. Only 18% (Hourihane et al, Bmj 316(7140):1271-1275, 1998) to 21% (Skolnick et al, J Allergy Clin Immunol 107(2):367-374, 2001) of children outgrow their peanut allergy (spontaneous development of tolerance), and there are no reliable predictors for resolution (Skolnick et al, supra 2001; Hourihane et al, supra 1998). Accidental ingestions of peanut in children with peanut allergy are common—50% within 1 year and 75% within 5 years (Bock and Atkins, J Allergy Clin Immunol 83(5):900-904, 1989). Most reactions from accidental ingestion are life threatening (Vander Leek et al, J Pediatr 137(6):749-755, 2000). Only 25% of peanut allergic patients were able to achieve complete avoidance without reaction in a five year period (Bock and Atkins, supra 1989). Therefore, patients with peanut allergy remain at significant ongoing risk of severe reactions.
There has been no effective long term treatment for food allergy. Management involves avoidance of the food concerned, early recognition of symptoms of an allergic reaction and initiation of appropriate emergency treatment of allergic reactions, particularly anaphylaxis. Adrenaline is the first line therapy for anaphylaxis and is available as a self injectable device, the EpiPen (Registered)/EpiPen Jr (Registered) in Australia (and other devices in USA). The EpiPen (Registered) or EpiPen Jr (Registered) must be replaced regularly (12-18 months) and requires specific training in its use (Mehr et al, Paediatr Allergy Immunol 18(5):448-452, 2006). As the majority of reactions to peanut are severe, most children with peanut allergy are prescribed an EpiPen (Registered) which must be carried with them at all times. The EpiPen (Registered) should be administered if accidental exposure results in a severe reaction involving the respiratory or cardiovascular systems (anaphylaxis). However, most patients who have been prescribed an EpiPen (Registered) fail to use it at the time of a severe allergic reaction. Only 71% of patients prescribed an EpiPen had their EpiPen with them, 10% of these had expired, and only 32% were able to demonstrate its correct use (Sicherer et al, Pediatrics 105(2):359-362, 2000). The burden of living with peanut allergy and its management is significant—children with peanut allergy are reported by their parents to have a poorer quality of life than children with rheumatological conditions (Primeau et al, Clin Exp Allergy 30(8):1135-1143, 2000). Therefore, for peanut allergy, the high risk of repeated severe life-threatening reactions and the limited reliability of EpiPen (Registered) being used for the treatment of acute reactions in the community highlight the need for long term treatment options that can achieve immune modulation and tolerance.
The mechanisms leading to the development of food allergy remain poorly understood. It is considered that food allergy is caused by a failure of oral tolerance. Oral tolerance can be induced by either a single high dose exposure to antigen or by repeated low dose exposures to antigen. High dose tolerance involves Fas-mediated apoptosis or anergy, while low dose tolerance is mediated by regulatory T cells (Treg). Recent studies suggest that anergy and induction of Treg may not be distinct mechanisms for tolerance, and most studies now focus on the role of Treg (reviewed in [Strobel and Mowat, Curr Opin Allergy Clin Immunol 6(3):207-213, 2006]). Several Treg subsets have been identified including Th3 cells, Tr1 cells, and CD4+CD25+ Treg. Th3 cells produce TGFβ and variable amounts of IL-4 and IL-10 (Chen et al, Science 265(5176):1237-1240, 1994). Tr1 cells secrete IL-10 (Groux et al, Nature 389(6652):737-742, 1997). CD4+CD25+ Treg express the transcription factor forkhead box P3 (FOXP3) and mediate their suppressive effects in part by cell surface bound TGFβ and to a lesser extent IL-10 (Chung et al, J Leukoc Biol 77(6):906-913, 2005). CD4+CD25+ Treg arise predominantly in the thymus, but may also develop in mesenteric lymph nodes, Peyer's patches and peripheral lymph nodes where they play a role in mucosal tolerance (Chung et al, supra 2005). Treg and the regulatory cytokines TGFβ and IL-10 have been shown to play important roles in oral tolerance induction and in food allergy. In a mouse model of food allergy, mice tolerized to β-lactoglobulin had higher numbers of antigen specific IgA secreting cells in Peyer's patches and higher levels of fecal IgA, as well as increased TGFβ and IL-10 production by Peyer's patch T cells as compared to sensitized mice (Frossard et al, J Allergy Clin Immunol 114(2):377-382, 2004).
Evidence of a role for Treg in tolerance induction and food allergy is also observed in human studies. Children with food allergy have fewer TGFβ+ lymphocytes in the duodenal epithelium and lamina propria (Perez-Machado et al, Eur J Immunol 33(8):2307-2315, 2003), and show reduced TGFβ expression by milk specific duodenal lymphocytes (Beyer et al, J Allergy Clin Immunol 109(4):7070-713, 2002). Similar findings have been reported for patients with non-IgE mediated food allergies (food protein induced enterocolitis) [Chung et al, J Allergy Clin Immunol 109(1):150-154, 2002]. In subjects with cow's milk allergy, resolution of allergy was associated with increased numbers of CD4+CD25+ T cells and reduced β-lactoglobulin induced proliferation compared to those with ongoing allergy (Karlsson et al, J Exp Med 199(12):1679-1688, 2004). In vitro depletion of these CD4+CD25+ cells led to increased β-lactoglobulin induced proliferation suggesting that induction of oral tolerance was related to increased CD4+CD25+ cells Treg (Karlsson et al, supra 2004). Oral tolerance is also associated with increased IFNγ (Tureanu et al, J Clin Invest 111(7):1065-1072, 2003). Comparison of peanut specific immune responses in normal children, children with peanut allergy, and peanut allergic children who had outgrown their allergy showed Th2 skewed responses in peanut allergy and Th1 skewed responses in oral tolerance (normal children and children who outgrew their peanut allergy) [Tureanu et al, supra 2003). These findings suggest that food allergy is associated with loss of tolerance, reduced Treg and TGFβ, as well as reduced Th1 and increased Th2 responses.
Immunotherapy is used for the long term treatment of asthma, allergic rhinitis and insect venom anaphylaxis. Subcutaneous immunotherapy (SCIT) has been shown to reduce clinical symptoms and induce prolonged tolerance to allergens by modulation of immune responses (Norman, J Allergy Clin Immunol 113(6):1013-1023, 2004; Schmidt-Weber and Blaser, Springer Semin Immunopathol 25(3-4):377-390, 2004). Mechanistic studies have shown that SCIT induces Treg and restores the disturbed balance of Th1/Th2 effector cells in allergic patients. SCIT leads to reduced allergen specific IgE, elevated allergen specific IgG4, reduced Th2 cytokine expression (IL-4, IL-5), and in most studies increased Th1 cytokine expression (IFNγ) [Norman, supra 2004; Schmidt-Weber and Blaser, supra 2004]. These effects have been shown to be mediated by increased numbers of CD4+CD25+ Treg, and induction of antigen specific CD4+CD25+ Treg with suppressive activity that is mediated by production of IL-10 and/or TGFβ (Norman, supra 2004; Schmidt-Weber and Blaser, supra 2004). Other immunological effects of SCIT include increased apoptosis of allergen specific Th2 cells, reduced tissue mast cell numbers and reduced serum levels of TNFα and IL-1β (Norman, supra 2004). Sublingual immunotherapy (SLIT) has also been shown to be effective in reducing clinical symptoms in respiratory allergy (asthma, rhinitis), however, immunological effects are less well characterized. Increased specific IgG4 and reduced specific IgE have been reported in some but not all studies (Norman, supra 2004). Oral immunotherapy (OIT) has not been consistently effective when used for the treatment of respiratory allergy and was largely abandoned for treatment of these conditions.
Various immunotherapy approaches have been attempted for the treatment of food allergy. Treatment with a humanized anti-IgE antibody was shown to increase the threshold dose required to induce a reaction, however, this approach is expensive and only provides a short term benefit without modifying the natural history of disease (Leung et al, N Engl J Med 348(11):986-993, 2003). SCIT for peanut anaphylaxis was effective in inducing desensitization and increasing the threshold dose required to induce a reaction (from 178 mg to 2805 mg, or from half a peanut to nine peanuts) in subjects who were able to continue on maintenance therapy (Nelson et al, J Allergy Clin Immunol 99(6 Pt1):744-751, 1997). However, serious systemic reactions were frequent (39% during maintenance) and this approach has been abandoned. Peptide and mutated protein SCIT are being investigated to avoid systemic reactions, however, translation to the clinic setting has been slow. SLIT has been used for the treatment of food allergy. A double blind placebo controlled study of SLIT with hazelnut extract for four months in 41 adults with hazelnut allergy resulted in an increased threshold for reaction in the active treatment group (from 2.29 g to 11.56 g) but not the placebo group (3.49 g to 4.14 g). 50% of the treatment group as compared to 9% of the placebo group were able to tolerate 20 g of hazelnut during oral challenge performed 8-12 weeks after immunotherapy had been discontinued, indicating long-lasting tolerance. As further evidence of immune tolerance, the active treatment group demonstrated increased serum levels of IL-10 and hazelnut specific IgG. SLIT with fresh kiwi pulp also resulted in prolonged clinical tolerance to kiwi in a 29 year old female who demonstrated protective effects from SLIT even after it had been discontinued for a period of four months (Kerzl et al, J Allergy Clin Immunol 119(2):507-508, 2007). These findings confirm the potential for SLIT as a treatment for food allergy in adults with evidence of immunomodulatory effects and prolonged clinical protection.
However, a major disadvantage of SLIT limiting its applicability in children is the need to hold the extract under the tongue for a period of time (1-3 minutes) before swallowing or discharging (Enrique et al, J Allergy Clin Immunol 116(5):1073-1079, 2005; Kerzl et al, supra 2007). OIT offers the advantage of improved acceptability and compliance in children (Buchanan et al, J Allergy Clin Immunol 119(1):199-205, 2007).
OIT has been used successfully for the treatment of food allergy. Case reports describe desensitization with OIT in milk allergy (Nucera et al, Dig Dis Sci 45(3):637-641, 2000; Bauer et al, Allergy 54(8):894-895, 1999). A 12 year old girl was desensitized to cow's milk and remained on OIT indefinitely (Bauer et al, supra 1999). A six year old girl with cow's milk allergy was desensitized to milk following four months of milk OIT, and experienced dramatic immunological changes including complete loss of SPT reaction to cow's milk, reduced serum levels of milk specific IgE, increased serum levels of milk specific IgG4 and IgA, as well as increased IFNγ and decreased IL-4 production in β-lactoglobulin stimulated PBMC cultures (Nucera et al, supra 2000). This suggests that OIT may induce tolerance in some circumstances. A large case control study of OIT in 51 patients aged 3-55 years with various food allergies showed successful desensitization in 83% (45/54) of subjects who remained on daily OIT (Patriarca et al, Aliment Pharmacol Ther 17(3):459-465, 2003). A reduction in peanut specific IgE and increase in peanut specific IgG4 was demonstrated suggesting the possibility of tolerance induction but this was not examined specifically (Patriarca et al, supra 2003). A double blind RCT of milk OIT (200 ml maintenance dose) for six months in 21 children with milk allergy reported successful desensitization to milk in 71% (15/21) [tolerated 200 ml of milk on a daily basis], and partial desensitization in 3/21 (14%) [tolerated 40-80 ml of milk] (Meglio et al, Allergy 59(9):980-987, 2004). None of the children demonstrated a reduction in milk specific IgE suggesting that tolerance was not achieved. In all of these previous studies, it is not certain whether OIT was effective in inducing tolerance since DBPC food challenges were not performed after immunotherapy was discontinued. Rolinck-Werninghaus reported two patients in whom discontinuation of milk or egg OIT following 37 wk and 41 wk of OIT respectively resulted in loss of desensitization, indicating that tolerance had not been achieved (Rolinck-Werninghaus et al, Allergy 60(10):1320-1322, 2005).
Studies and investigations aimed at developing protocols to manage allergic disorders have been focused on prevention rather than treatment and have been based on animal models which poorly replicate the human allergic disease condition (e.g.: Schabussora and Widermann, Curr Opin Allergy Clin Immunol 8(6):557-564, 2008; Daniel et al, Allergy 52(11):1237-1242, 2007; and Shida et al, Clin Exp Allergy 32:563-570, 2002). Neither a prevention nor treatment protocol based on probiotics or prebiotics alone has achieved large scale success. Initial studies of probiotics or prebiotics for the prevention of eczema had provided promising results (Osborne and Sinn, Probiotics in infants for prevention of allergic disease and food hypersensitivity (Review), Cochrane Database Syst Rev Art No. CD006475, 2007; Osborne and Sinn, Probiotics in infants for prevention of allergic disease and food hypersensitivity (Review), Cochrane Database Syst Rev Art No. CD006474, 2007). However, probiotics for the treatment of eczema has not proven successful as have the use of probiotics or prebiotics alone for the prevention or treatment of food allergy (Boyle et al, Syst Rev, Oct. 8, 2008 Issue 4, CD006135).
New strategies to treat allergies which enhance tolerance induction are required.